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Extensively drug-resistant tuberculosis treatment outcome in Iran: a case series of seven patients
International Journal of Infectious Diseases 14 (2010) e399–e402
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Extensively drug-resistant tuberculosis treatment outcome in Iran: a case series of seven patients Mohammad R. Masjedi, Payam Tabarsi *, Parvaneh Baghaei, Sara Jalali, Parisa Farnia, Ehsan Chitsaz, Majid Amiri, Davood Mansouri, Ali A. Velayati Department of TB and Respiratory Infection, National Research Institute of TB and Lung Disease, Masih Daneshvari Hospital, Niavaran-Darabad, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 December 2007 Received in revised form 30 July 2009 Accepted 30 July 2009
Background: Extensively drug-resistant tuberculosis (XDR-TB) has recently been identified as a major threat to global health. XDR-TB poses a risk of higher failure rates and death during TB treatment. We report herein the outcomes of XDR-TB in patients treated with the standardized regimen in Iran. Patients and methods: Between 2002 and 2006, seven patients were diagnosed with XDR-TB. All patients were treated with the standardized second-line regimen containing cycloserine, prothionamide, amikacin, and ofloxacin. First-line drugs, such as ethambutol and pyrazinamide, were added to the regimen if drug susceptibility testing showed sensitivity to these drugs. Results: Four (57.1%) patients were male. All seven patients were HIV-negative. The patient age range was 22–79 years. Of the seven cases, the final outcome was ‘cure’ in two (28.6%), ‘relapse’ in one, ‘treatment failure’ in one, and ‘death’ in two; the outcome for one patient was unknown. Conclusion: Our study shows a poor prognosis in patients with XDR-TB. This indicates the necessity of detecting XDR-TB cases earlier, as well as the need to gain access to more second-line agents. This is particularly important in resource-limited settings in order to administer individualized regimens. ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Tuberculosis XDR Outcome
1. Introduction Approximately nine million people will get tuberculosis (TB) annually, and more than two million TB-related deaths are reported annually worldwide.1 Despite meticulous efforts to control TB disease in most regions, the emergence of drug resistance in mycobacterial strains represents a major obstacle to attaining efficient TB control. Multidrug-resistant tuberculosis (MDR-TB) is defined as resistance to at least isoniazid and rifampin, the two most potent first-line drugs used in the treatment of TB. Meanwhile, extensively drug-resistant TB (XDR-TB) has emerged as a catastrophic condition in the management of TB. XDR-TB has recently been identified as a major threat to global health. The problem is complicated, as XDRTB poses a risk of higher failure rates and death during TB treatment, mostly due to the lack of novel drugs active against the resistant strains.2–4 The revised definition of XDR-TB comprises resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and
* Corresponding author. Tel.: +98 21 22296362. E-mail address: [email protected] (P. Tabarsi).
at least one of the three second-line injectable drugs, including amikacin, capreomycin, and kanamycin.5–7 However, innumerable questions remain regarding the management of XDR-TB, including those concerning appropriate therapy, novel medications, and treatment outcomes and prognosis. To-date little information has been reported worldwide on the outcome of treatment in XDR-TB cases. Since the World Health Organization (WHO) guidelines recommend the use of at least four active drugs in those with MDRTB, XDR-TB may appear to be untreatable by international standards. Accordingly, the available data show a high mortality rate associated with XDR-TB.8 Nevertheless, in some studies ‘cure’ or ‘treatment completion’ has been reported to be as high as 31– 61% in XDR-TB cases.9 We report herein the outcome of the first cohort of XDR-TB patients in Iran. 2. Methods and results Second-line drugs for the treatment of MDR-TB have been available in Iran since 2002.10,11 According to Iran’s National TB Treatment Protocol, all TB patients with WHO regimen category I (CAT I) and category II (CAT II) failures are referred to our center for evaluation and treatment of MDR-TB.
1201-9712/$36.00 – see front matter ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.07.002
M.R. Masjedi et al. / International Journal of Infectious Diseases 14 (2010) e399–e402
e400
disease or previous illnesses. Serologic testing showed that she was negative for HIV. She had received the CAT I regimen, and due to its failure, CAT II for 8 months. DST results showed resistance to all first-line anti-TB drugs. Similar to case 1, DST results for the second-line agents showed resistance to all second-line drugs, except for cycloserine (Table 1). In April 2006, she was hospitalized at our center as a CAT II treatment failure case. Similarly to case 1, she received the standardized regimen and underwent treatment for 24 months. Her culture first turned negative after 6 months of treatment. She received 6 months of amikacin after her sputum became negative. The patient did not develop any adverse drug reactions during this treatment. As a result of five negative sputum smears and cultures in the last 12 months of treatment, she was categorized as ‘cure’ for treatment outcome. At her one-year follow-up visit, she did not have any complaints or signs suggestive of TB recurrence.
This study was carried out at the National Research Institute of Tuberculosis and Lung Disease (NRITLD) at Masih Daneshvari Hospital, the sole national referral center for TB in Iran, which includes the National Mycobacteriologic Reference Laboratory. All patients with documented MDR-TB based on drug susceptibility testing (DST) are treated with the standard second-line regimen, consisting of cycloserine, prothionamide, amikacin, and ofloxacin. First-line drugs such as ethambutol and pyrazinamide are added to the regimen if the DST shows sensitivity to these drugs. For those patients with MDR-TB, second-line drug susceptibility tests are performed as well. Between 2002 and 2006, 105 patients with suspected MDR-TB were identified at Masih Daneshvari Hospital in Tehran, Iran. Of these patients, seven (6.6%) were diagnosed with XDR-TB; their DST results became available later in the course of therapy. A brief description of each case follows. 3. Case 1
5. Case 3 A 22-year-old man presented to our center with a productive cough, fever, nocturnal perspiration, and weight loss since 2002. He was originally from the neighboring country of the Republic of Azerbaijan. The patient did not have any history of contact or exposure to suspected TB patients, nor did he have a history of other previous illnesses or any underlying diseases. He was negative for HIV infection. He had been receiving irregular CAT I and CAT II treatment regimens for his TB and was referred to our center as a CAT II treatment failure. DST showed resistance to all first-line anti-TB drugs. Surprisingly, later DST for second-line agents demonstrated resistance to all the second-line drugs except for cycloserine and ethionamide (Table 1). When first seen at our center as a likely MDR-TB case, he was hospitalized and then underwent anti-TB treatment with the standardized regimen containing cycloserine, amikacin, ofloxacin, and prothionamide. Treatment started in August 2004 and lasted for a complete course of 24 months. His cultures first turned negative after 4 months of treatment. Amikacin was administered for 7 months after his sputum turned negative. He did not develop any adverse effects attributed to the anti-TB drugs during the course of treatment. Having completed the treatment course, five further sputum smears and cultures for Mycobacterium tuberculosis (MTB) were negative. In accordance with the negative mycobacteriologic studies, along with radiographic improvement on chest X-ray, his treatment outcome was categorized as ‘cure’. He showed no symptoms or signs suggestive of recurrence of the infection at the next two consecutive annual follow-up visits.
A 65-year-old Iranian man presented to our center with a productive cough and chest pain since 2001. He was negative for HIV and was otherwise healthy. He had received three courses of therapy (CAT I twice for 6 months and CAT II for 8 months) irregularly over the past year. According to the DST results, he was resistant to all first-line anti-TB drugs. Also, further DST showed resistance to all secondline anti-TB drugs, identifying extensive-drug resistance (Table 1). His treatment was started in February 2003 and he received the standard regimen, with amikacin for 10 months. After 2 years, because of two occurrences of negative sputum smear and culture at the end of the second year of treatment, his treatment was terminated and he was categorized as ‘cure’. Unfortunately, 6 months after treatment termination, his general condition deteriorated and the disease manifestations were aggravated. In further evaluations, his sputum smear and culture became positive again. Due to limitations in access to diverse second-line anti-TB agents in Iran, the patient was retreated with the same standard regimen. Having undergone more than a year of his retreatment course, his sputum smear and culture has, to-date, been repeatedly positive. Using DNA fingerprinting, the strain of TB responsible for his recent complaints was identified as the same as the first infecting strain. Thus, he has been categorized as a ‘relapse’ case. 6. Case 4
4. Case 2
A 55-year-old female patient presented to our center with a productive cough, fever, chills, dyspnea, and weight loss, with a history of TB since 2001. She was referred to our center regarding her history of irregular treatment with CAT I and CAT II regimens.
A 63-year-old woman presented to our center with a productive cough since 2004. She was Iranian and did not have any underlying Table 1 Drug susceptibility tests and outcomes of patients with XDR-TB in Iran
1 2 3 4 5 6a 7
Age (years)
Sex
Nation
OFX
CIP
CS
AM
KM
ETO
PAS
CM
PZA
EMB
Outcome
22 63 63 55 64 79 24
M F M F M F M
Azerbaijan Iran Iran Afghanistan Iran Iran Azerbaijan
R R R R R R R
R R R R R R R
S S R S S R R
R R R R R R R
R R R R R S R
S R R R S R R
R R R S S S R
R R R R R R R
R R R R S R R
R R R S S R R
Cure Cure Relapse Failure Death Death Unknown
M, male; F, female; S, sensitive; R, resistant; OFX, ofloxacin; CIP, ciprofloxacin; CS, cycloserine; AM, amikacin; KM, kanamycin; ETO, ethionamide; PAS, para-aminosalicylic acid; CM, capreomycin; PZA, pyrazinamide; EMB, ethambutol. a Primary XDR-TB.
M.R. Masjedi et al. / International Journal of Infectious Diseases 14 (2010) e399–e402
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A 24-year-old man who had come from Republic of Azerbaijan, presented to our center with a productive cough, nocturnal perspiration, and weight loss. He had no underlying problem and was referred because of CAT I treatment failure. DST for his firstline agents showed resistance to all the drugs. Moreover, DST also showed resistance to all second-line drugs (Table 1). During the course of treatment and because of his personal consent, the patient was transferred to Azerbaijan for treatment continuation. We have no data on his later condition and hence his final outcome is unknown.
seven patients were HIV-negative. The mean age of the patients was 52.85 21.61 years (range 22–79 years). One of the seven patients was diagnosed as having primary XDR-TB, with no history of previous treatment and no known close contact. Of the remaining six patients, all had a history of previous anti-TB treatment. Our data show that XDR-TB developed predominantly in cases who had received prior anti-TB medication. This mandates further consideration of anti-TB medication as a potential cause in the creation of the more difficult-to-treat drug-resistant strains (i.e., XDR-TB). The most important factor in controlling the development of drug-resistant TB is the completion of treatment, as poor compliance has been identified as the main cause; this may also be true in our setting.7,12 The currently available data from a variety of studies in different settings indicate that approximately 4–19% of assumed MDR-TB isolates are in fact XDR-TB.13 This proportion was 6.7% in our study. All patients were treated with the aforementioned standardized second-line regimen, as individualized treatment could not be administered due to the unavailability of other second-line agents in Iran. As MDR-TB persists as a growing problem, XDR-TB is also becoming more prevalent among infected patients.2,7 MDR-TB is now found to have different outcomes in various settings. According to our recent report on MDR-TB treatment outcomes with the standardized regimen, approximately 67% of cases reach a successful outcome.11,14 Although there has been little information reported regarding the outcome of treatment in XDR-TB cases, successful cases are few. In addition, co-infection with HIV greatly increases the chances of death.8,15 Since the seven patients in this study were not infected with HIV, we were able to assess more directly the treatment outcome of XDR-TB in patients with fewer confounding factors. Our study shows a poor prognosis in patients with XDR-TB, since only two patients out of the seven were successfully treated without relapse. Failure and/or death appear to be more likely outcomes, even with the standard second-line drug regimen. Similar results are being reported worldwide.7,16 However, data are scarce on whether, for XDR-TB cases, the standardized regimen (either the same as that used for MDR-TB or another standardized regimen different from the former) should be used or whether one should directly address the issue with individualized regimens specified for each case according to his/her second-line DST results. Our study findings show that there was no obvious correlation between the drugs to which a case was resistant and his/her final treatment outcome. The small number of cases in our study may have influenced these results. In a study performed in the USA, 17 out of 922 (2%) MDR-TB patients were identified as having XDR-TB between the years 2000 and 2006. Six (35%) patients were noted as successfully cured. The study also showed that two (12%) patients died during treatment; the outcomes of nine (52.9%) patients were not reported. As compared to the US study, our results show a slightly lower cure rate (28.6%) and a higher death rate (28.6%). The US study also showed a high rate of primary XDR-TB: 14 (82%) in the US compared to one (14.3%) in our study.15 XDR-TB has proven to be difficult to cure. Further studies on larger sample sizes should be carried out in order to better assess the likelihood of survival.
10. Discussion
11. Conclusions
Of the 105 patients seen between 2002 and 2006, seven (6.6%) were diagnosed with XDR-TB. Four (57.1%) patients were male. All
The treatment of XDR-TB is a complex issue. There have been few recommendations for the treatment of XDR-TB, and amongst
She had come to Iran from another neighboring country, Afghanistan. She did not report any previous illnesses or underlying conditions. Her HIV test was negative. Cultures were resistant to all first-line agents except for ethambutol, to which her DST showed sensitivity. DST showed resistance to all second-line agents with the exception of cycloserine and para-aminosalicylic acid (PAS) (Table 1). Treatment with the standard regimen was started in April 2006. Despite receiving treatment for more than 18 months, her sputum smears and cultures have remained positive. Therefore, she is considered a treatment ‘failure’ case. 7. Case 5 A 64-year-old man presented to our center with a productive cough, hemoptysis, anorexia, and weight loss since 1999. He was Iranian and had no history of underlying problems. He was negative for HIV. He had received one course of 6-month anti-TB treatment and was referred to our center because of CAT I treatment failure. DST for the first-line agents showed resistance to isoniazid, rifampin, and streptomycin, but sensitivity to ethambutol and pyrazinamide. DST for second-line agents revealed resistance to ofloxacin, ciprofloxacin, amikacin, kanamycin and capreomycin, while showing sensitivity to other second-line agents such as cycloserine, ethionamide, and PAS (Table 1). From February 2004, he received the standard regimen, including ethambutol and pyrazinamide. Amikacin was administered for 7 months. During the course of treatment he developed neurologic adverse effects as a result of the cycloserine, hence his cycloserine was discontinued. Seven months after treatment was initiated, his condition became aggravated and he died due to respiratory arrest. 8. Case 6 A 79-year-old woman presented to our center with a productive cough and dyspnea. She was Iranian and lived in a day-care residence. She had no history of prior TB or being treated for such a disease. DST showed resistance to all first-line drugs. DST for secondline drugs showed sensitivity to kanamycin and capreomycin only, and showed resistance to all other second-line agents (Table 1). She was categorized as a primary XDR-TB case, presenting for the first time to our center. She was started on the standard regimen of second-line agents. However, one week after treatment initiation, she developed acute respiratory distress syndrome (ARDS) and died. 9. Case 7
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these, no favorable results have been reported. Likewise, our study showed unfavorable results with standardized regimens. Early detection of infection and access to affordable drugs worldwide will help prevent the progression of this disease. Also, the development of novel and more rapid DST methods is necessary, and these should be made widely available in order to detect XDR-TB cases earlier. Conflict of interest: No conflict of interest to declare. References 1. Dye C. Global epidemiology of tuberculosis. Lancet 2006;367:938–40. 2. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martin-Casabona N, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007;13:380–7. 3. Masjedi MR, Farnia P, Sorooch S, Pooramiri MV, Mansoori SD, Zarifi AZ, et al. Extensively drug-resistant tuberculosis: 2 years of surveillance in Iran. Clin Infect Dis 2006;43:841–7. 4. Jones KD, Hesketh T, Yudkin J. Extensively drug-resistant tuberculosis in subSaharan Africa: an emerging public-health concern. Trans R Soc Trop Med Hyg 2008;102:219–24. 5. Centers for Disease Control and Prevention. Revised definition of extensively drug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 2006;55:1176. 6. World Health Organization. Case definition for extensively drug-resistant tuberculosis. Wkly Epidemiol Rec 2006;81:408.
7. Dorman S, Chaisson R. From magic bullets back to the Magic Mountain: the rise of extensively drug-resistant tuberculosis. Nat Med 2007;13:295–8. 8. Ghandi NR, Moll A, Strum AW, Pawinski R, Govender T, Lalloo U, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368: 1575–80. 9. Migliori GB, Besozzi G, Girardi E, Kliiman K, Lange C, Toungoussova OS, et al. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J 2007;30:623–6. 10. Mirsaeidi SM, Tabarsi P, Khoshnood K, Pooramiri MV, Rowhani-Rahbar A, Mansoori SD, et al. Treatment of multiple drug-resistant tuberculosis (MDRTB) in Iran. Int J Infect Dis 2005;9:317–22. 11. Masjedi MR, Tabarsi P, Chitsaz E, Baghaei P, Mirsaiedi M, Pooramiri MV, et al. Outcome of treatment of MDR-TB patients with standardized regimens: Iran’s experience 2002–2006. Int J Tuberc Lung Dis 2008;12:750–5. 12. Hamilton CD, Sterling TR, Blumberg HM, Leonard M, McAuley J, Schlossberg D, et al. Extensively drug-resistant tuberculosis: are we learning from history or repeating it? Clin Infect Dis 2007;45:338–42. 13. Raviglione MC, Smith IM. XDR tuberculosis—implications for global public health. N Engl J Med 2007;356:656–9. 14. Yew WW, Leung CC. Management of multi-drug-resistant tuberculosis: update 2007. Respirology 2008;13:21–46. 15. Centers for Disease Control and Prevention. Extensively drug-resistant tuberculosis—United States, 1993–2006. MMWR Morb Mortal Wkly Rep 2007;56: 250–3. 16. Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep 2006;55:301–5.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Extensively drug-resistant tuberculosis treatment outcome in Iran: a case series of seven patients Mohammad R. Masjedi, Payam Tabarsi *, Parvaneh Baghaei, Sara Jalali, Parisa Farnia, Ehsan Chitsaz, Majid Amiri, Davood Mansouri, Ali A. Velayati Department of TB and Respiratory Infection, National Research Institute of TB and Lung Disease, Masih Daneshvari Hospital, Niavaran-Darabad, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 December 2007 Received in revised form 30 July 2009 Accepted 30 July 2009
Background: Extensively drug-resistant tuberculosis (XDR-TB) has recently been identified as a major threat to global health. XDR-TB poses a risk of higher failure rates and death during TB treatment. We report herein the outcomes of XDR-TB in patients treated with the standardized regimen in Iran. Patients and methods: Between 2002 and 2006, seven patients were diagnosed with XDR-TB. All patients were treated with the standardized second-line regimen containing cycloserine, prothionamide, amikacin, and ofloxacin. First-line drugs, such as ethambutol and pyrazinamide, were added to the regimen if drug susceptibility testing showed sensitivity to these drugs. Results: Four (57.1%) patients were male. All seven patients were HIV-negative. The patient age range was 22–79 years. Of the seven cases, the final outcome was ‘cure’ in two (28.6%), ‘relapse’ in one, ‘treatment failure’ in one, and ‘death’ in two; the outcome for one patient was unknown. Conclusion: Our study shows a poor prognosis in patients with XDR-TB. This indicates the necessity of detecting XDR-TB cases earlier, as well as the need to gain access to more second-line agents. This is particularly important in resource-limited settings in order to administer individualized regimens. ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Tuberculosis XDR Outcome
1. Introduction Approximately nine million people will get tuberculosis (TB) annually, and more than two million TB-related deaths are reported annually worldwide.1 Despite meticulous efforts to control TB disease in most regions, the emergence of drug resistance in mycobacterial strains represents a major obstacle to attaining efficient TB control. Multidrug-resistant tuberculosis (MDR-TB) is defined as resistance to at least isoniazid and rifampin, the two most potent first-line drugs used in the treatment of TB. Meanwhile, extensively drug-resistant TB (XDR-TB) has emerged as a catastrophic condition in the management of TB. XDR-TB has recently been identified as a major threat to global health. The problem is complicated, as XDRTB poses a risk of higher failure rates and death during TB treatment, mostly due to the lack of novel drugs active against the resistant strains.2–4 The revised definition of XDR-TB comprises resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and
* Corresponding author. Tel.: +98 21 22296362. E-mail address: [email protected] (P. Tabarsi).
at least one of the three second-line injectable drugs, including amikacin, capreomycin, and kanamycin.5–7 However, innumerable questions remain regarding the management of XDR-TB, including those concerning appropriate therapy, novel medications, and treatment outcomes and prognosis. To-date little information has been reported worldwide on the outcome of treatment in XDR-TB cases. Since the World Health Organization (WHO) guidelines recommend the use of at least four active drugs in those with MDRTB, XDR-TB may appear to be untreatable by international standards. Accordingly, the available data show a high mortality rate associated with XDR-TB.8 Nevertheless, in some studies ‘cure’ or ‘treatment completion’ has been reported to be as high as 31– 61% in XDR-TB cases.9 We report herein the outcome of the first cohort of XDR-TB patients in Iran. 2. Methods and results Second-line drugs for the treatment of MDR-TB have been available in Iran since 2002.10,11 According to Iran’s National TB Treatment Protocol, all TB patients with WHO regimen category I (CAT I) and category II (CAT II) failures are referred to our center for evaluation and treatment of MDR-TB.
1201-9712/$36.00 – see front matter ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.07.002
M.R. Masjedi et al. / International Journal of Infectious Diseases 14 (2010) e399–e402
e400
disease or previous illnesses. Serologic testing showed that she was negative for HIV. She had received the CAT I regimen, and due to its failure, CAT II for 8 months. DST results showed resistance to all first-line anti-TB drugs. Similar to case 1, DST results for the second-line agents showed resistance to all second-line drugs, except for cycloserine (Table 1). In April 2006, she was hospitalized at our center as a CAT II treatment failure case. Similarly to case 1, she received the standardized regimen and underwent treatment for 24 months. Her culture first turned negative after 6 months of treatment. She received 6 months of amikacin after her sputum became negative. The patient did not develop any adverse drug reactions during this treatment. As a result of five negative sputum smears and cultures in the last 12 months of treatment, she was categorized as ‘cure’ for treatment outcome. At her one-year follow-up visit, she did not have any complaints or signs suggestive of TB recurrence.
This study was carried out at the National Research Institute of Tuberculosis and Lung Disease (NRITLD) at Masih Daneshvari Hospital, the sole national referral center for TB in Iran, which includes the National Mycobacteriologic Reference Laboratory. All patients with documented MDR-TB based on drug susceptibility testing (DST) are treated with the standard second-line regimen, consisting of cycloserine, prothionamide, amikacin, and ofloxacin. First-line drugs such as ethambutol and pyrazinamide are added to the regimen if the DST shows sensitivity to these drugs. For those patients with MDR-TB, second-line drug susceptibility tests are performed as well. Between 2002 and 2006, 105 patients with suspected MDR-TB were identified at Masih Daneshvari Hospital in Tehran, Iran. Of these patients, seven (6.6%) were diagnosed with XDR-TB; their DST results became available later in the course of therapy. A brief description of each case follows. 3. Case 1
5. Case 3 A 22-year-old man presented to our center with a productive cough, fever, nocturnal perspiration, and weight loss since 2002. He was originally from the neighboring country of the Republic of Azerbaijan. The patient did not have any history of contact or exposure to suspected TB patients, nor did he have a history of other previous illnesses or any underlying diseases. He was negative for HIV infection. He had been receiving irregular CAT I and CAT II treatment regimens for his TB and was referred to our center as a CAT II treatment failure. DST showed resistance to all first-line anti-TB drugs. Surprisingly, later DST for second-line agents demonstrated resistance to all the second-line drugs except for cycloserine and ethionamide (Table 1). When first seen at our center as a likely MDR-TB case, he was hospitalized and then underwent anti-TB treatment with the standardized regimen containing cycloserine, amikacin, ofloxacin, and prothionamide. Treatment started in August 2004 and lasted for a complete course of 24 months. His cultures first turned negative after 4 months of treatment. Amikacin was administered for 7 months after his sputum turned negative. He did not develop any adverse effects attributed to the anti-TB drugs during the course of treatment. Having completed the treatment course, five further sputum smears and cultures for Mycobacterium tuberculosis (MTB) were negative. In accordance with the negative mycobacteriologic studies, along with radiographic improvement on chest X-ray, his treatment outcome was categorized as ‘cure’. He showed no symptoms or signs suggestive of recurrence of the infection at the next two consecutive annual follow-up visits.
A 65-year-old Iranian man presented to our center with a productive cough and chest pain since 2001. He was negative for HIV and was otherwise healthy. He had received three courses of therapy (CAT I twice for 6 months and CAT II for 8 months) irregularly over the past year. According to the DST results, he was resistant to all first-line anti-TB drugs. Also, further DST showed resistance to all secondline anti-TB drugs, identifying extensive-drug resistance (Table 1). His treatment was started in February 2003 and he received the standard regimen, with amikacin for 10 months. After 2 years, because of two occurrences of negative sputum smear and culture at the end of the second year of treatment, his treatment was terminated and he was categorized as ‘cure’. Unfortunately, 6 months after treatment termination, his general condition deteriorated and the disease manifestations were aggravated. In further evaluations, his sputum smear and culture became positive again. Due to limitations in access to diverse second-line anti-TB agents in Iran, the patient was retreated with the same standard regimen. Having undergone more than a year of his retreatment course, his sputum smear and culture has, to-date, been repeatedly positive. Using DNA fingerprinting, the strain of TB responsible for his recent complaints was identified as the same as the first infecting strain. Thus, he has been categorized as a ‘relapse’ case. 6. Case 4
4. Case 2
A 55-year-old female patient presented to our center with a productive cough, fever, chills, dyspnea, and weight loss, with a history of TB since 2001. She was referred to our center regarding her history of irregular treatment with CAT I and CAT II regimens.
A 63-year-old woman presented to our center with a productive cough since 2004. She was Iranian and did not have any underlying Table 1 Drug susceptibility tests and outcomes of patients with XDR-TB in Iran
1 2 3 4 5 6a 7
Age (years)
Sex
Nation
OFX
CIP
CS
AM
KM
ETO
PAS
CM
PZA
EMB
Outcome
22 63 63 55 64 79 24
M F M F M F M
Azerbaijan Iran Iran Afghanistan Iran Iran Azerbaijan
R R R R R R R
R R R R R R R
S S R S S R R
R R R R R R R
R R R R R S R
S R R R S R R
R R R S S S R
R R R R R R R
R R R R S R R
R R R S S R R
Cure Cure Relapse Failure Death Death Unknown
M, male; F, female; S, sensitive; R, resistant; OFX, ofloxacin; CIP, ciprofloxacin; CS, cycloserine; AM, amikacin; KM, kanamycin; ETO, ethionamide; PAS, para-aminosalicylic acid; CM, capreomycin; PZA, pyrazinamide; EMB, ethambutol. a Primary XDR-TB.
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A 24-year-old man who had come from Republic of Azerbaijan, presented to our center with a productive cough, nocturnal perspiration, and weight loss. He had no underlying problem and was referred because of CAT I treatment failure. DST for his firstline agents showed resistance to all the drugs. Moreover, DST also showed resistance to all second-line drugs (Table 1). During the course of treatment and because of his personal consent, the patient was transferred to Azerbaijan for treatment continuation. We have no data on his later condition and hence his final outcome is unknown.
seven patients were HIV-negative. The mean age of the patients was 52.85 21.61 years (range 22–79 years). One of the seven patients was diagnosed as having primary XDR-TB, with no history of previous treatment and no known close contact. Of the remaining six patients, all had a history of previous anti-TB treatment. Our data show that XDR-TB developed predominantly in cases who had received prior anti-TB medication. This mandates further consideration of anti-TB medication as a potential cause in the creation of the more difficult-to-treat drug-resistant strains (i.e., XDR-TB). The most important factor in controlling the development of drug-resistant TB is the completion of treatment, as poor compliance has been identified as the main cause; this may also be true in our setting.7,12 The currently available data from a variety of studies in different settings indicate that approximately 4–19% of assumed MDR-TB isolates are in fact XDR-TB.13 This proportion was 6.7% in our study. All patients were treated with the aforementioned standardized second-line regimen, as individualized treatment could not be administered due to the unavailability of other second-line agents in Iran. As MDR-TB persists as a growing problem, XDR-TB is also becoming more prevalent among infected patients.2,7 MDR-TB is now found to have different outcomes in various settings. According to our recent report on MDR-TB treatment outcomes with the standardized regimen, approximately 67% of cases reach a successful outcome.11,14 Although there has been little information reported regarding the outcome of treatment in XDR-TB cases, successful cases are few. In addition, co-infection with HIV greatly increases the chances of death.8,15 Since the seven patients in this study were not infected with HIV, we were able to assess more directly the treatment outcome of XDR-TB in patients with fewer confounding factors. Our study shows a poor prognosis in patients with XDR-TB, since only two patients out of the seven were successfully treated without relapse. Failure and/or death appear to be more likely outcomes, even with the standard second-line drug regimen. Similar results are being reported worldwide.7,16 However, data are scarce on whether, for XDR-TB cases, the standardized regimen (either the same as that used for MDR-TB or another standardized regimen different from the former) should be used or whether one should directly address the issue with individualized regimens specified for each case according to his/her second-line DST results. Our study findings show that there was no obvious correlation between the drugs to which a case was resistant and his/her final treatment outcome. The small number of cases in our study may have influenced these results. In a study performed in the USA, 17 out of 922 (2%) MDR-TB patients were identified as having XDR-TB between the years 2000 and 2006. Six (35%) patients were noted as successfully cured. The study also showed that two (12%) patients died during treatment; the outcomes of nine (52.9%) patients were not reported. As compared to the US study, our results show a slightly lower cure rate (28.6%) and a higher death rate (28.6%). The US study also showed a high rate of primary XDR-TB: 14 (82%) in the US compared to one (14.3%) in our study.15 XDR-TB has proven to be difficult to cure. Further studies on larger sample sizes should be carried out in order to better assess the likelihood of survival.
10. Discussion
11. Conclusions
Of the 105 patients seen between 2002 and 2006, seven (6.6%) were diagnosed with XDR-TB. Four (57.1%) patients were male. All
The treatment of XDR-TB is a complex issue. There have been few recommendations for the treatment of XDR-TB, and amongst
She had come to Iran from another neighboring country, Afghanistan. She did not report any previous illnesses or underlying conditions. Her HIV test was negative. Cultures were resistant to all first-line agents except for ethambutol, to which her DST showed sensitivity. DST showed resistance to all second-line agents with the exception of cycloserine and para-aminosalicylic acid (PAS) (Table 1). Treatment with the standard regimen was started in April 2006. Despite receiving treatment for more than 18 months, her sputum smears and cultures have remained positive. Therefore, she is considered a treatment ‘failure’ case. 7. Case 5 A 64-year-old man presented to our center with a productive cough, hemoptysis, anorexia, and weight loss since 1999. He was Iranian and had no history of underlying problems. He was negative for HIV. He had received one course of 6-month anti-TB treatment and was referred to our center because of CAT I treatment failure. DST for the first-line agents showed resistance to isoniazid, rifampin, and streptomycin, but sensitivity to ethambutol and pyrazinamide. DST for second-line agents revealed resistance to ofloxacin, ciprofloxacin, amikacin, kanamycin and capreomycin, while showing sensitivity to other second-line agents such as cycloserine, ethionamide, and PAS (Table 1). From February 2004, he received the standard regimen, including ethambutol and pyrazinamide. Amikacin was administered for 7 months. During the course of treatment he developed neurologic adverse effects as a result of the cycloserine, hence his cycloserine was discontinued. Seven months after treatment was initiated, his condition became aggravated and he died due to respiratory arrest. 8. Case 6 A 79-year-old woman presented to our center with a productive cough and dyspnea. She was Iranian and lived in a day-care residence. She had no history of prior TB or being treated for such a disease. DST showed resistance to all first-line drugs. DST for secondline drugs showed sensitivity to kanamycin and capreomycin only, and showed resistance to all other second-line agents (Table 1). She was categorized as a primary XDR-TB case, presenting for the first time to our center. She was started on the standard regimen of second-line agents. However, one week after treatment initiation, she developed acute respiratory distress syndrome (ARDS) and died. 9. Case 7
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these, no favorable results have been reported. Likewise, our study showed unfavorable results with standardized regimens. Early detection of infection and access to affordable drugs worldwide will help prevent the progression of this disease. Also, the development of novel and more rapid DST methods is necessary, and these should be made widely available in order to detect XDR-TB cases earlier. Conflict of interest: No conflict of interest to declare. References 1. Dye C. Global epidemiology of tuberculosis. Lancet 2006;367:938–40. 2. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martin-Casabona N, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007;13:380–7. 3. Masjedi MR, Farnia P, Sorooch S, Pooramiri MV, Mansoori SD, Zarifi AZ, et al. Extensively drug-resistant tuberculosis: 2 years of surveillance in Iran. Clin Infect Dis 2006;43:841–7. 4. Jones KD, Hesketh T, Yudkin J. Extensively drug-resistant tuberculosis in subSaharan Africa: an emerging public-health concern. Trans R Soc Trop Med Hyg 2008;102:219–24. 5. Centers for Disease Control and Prevention. Revised definition of extensively drug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 2006;55:1176. 6. World Health Organization. Case definition for extensively drug-resistant tuberculosis. Wkly Epidemiol Rec 2006;81:408.
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